Fobrepodacin

本文梳理了近一个月（2024年10月16日～2024年11月15日）在研药物的临床试验取得不佳（研发成功率降低）进展的情况，同时，对部分药物的研究情况进行简述和分析，供研发人员参考。 据统计，在检索时间范围内，共有10个药物的临床试验数据进展不佳（表1），其中有5个处于暂停阶段，分别有2个处于Ⅱ、Ⅲ期阶段。适应症涉及库欣氏综合征、急性髓性白血病、艾滋病、抑郁症、近视黄斑变性、鼻息肉病、非结核分枝杆菌等。以下对部分药物的研究进展不佳原因进行简要介绍。 表1：近一个月（2024年10月16日～2024年11月15日）临床试验数据不佳的药物 Uproleselan 近期，根据GlycoMimetics公布的关于美国国家癌症研究所（NCI）和肿瘤临床试验联盟正在进行的适应性Ⅱ/Ⅲ期试验（NCT03701308）的Ⅱ期分析，在新诊断的适合接受强化化疗的60岁或60岁以上AML成人患者中，与单独化疗相比，Uproleselan和阿糖胞苷+柔红霉素（7+3）化疗联合治疗未能引起无事件生存期（EFS）的统计学显著改善。 Ⅱ期临床分析结果显示，Uproleselan组合未达到试验的主要终点EFS。NCI和肿瘤临床试验联盟的研究者正在努力进一步评价试验结果，这将包括亚组分析数据的评估，以确定是否有任何疗效信号需要进一步研究。此外，来自Ⅱ/Ⅲ期试验的主要数据将在未来的医学会议上分享。 2024年5月初，GlycoMimetics宣布，在一项全球性Ⅲ期试验（NCT03616470）纳入的R/R AML患者（n=388）意向治疗人群中，Uproleselan联合化疗与单独化疗相比，未能在总生存期（OS）方面取得统计学意义上的显著改善。初步结果显示，联合用药的中位OS为13个月，而单独化疗的中位OS为12.3个月。在安全性方面，不良反应与试验中使用的化疗药物的已知毒性特征一致。该研究已被终止。 这项随机、双盲、安慰剂对照的Ⅲ期研究评估了R/R AML患者接受Uproleselan与MEC（米托蒽醌、依托泊苷和阿糖胞苷）或FAI（氟达拉滨、阿糖胞苷和去甲氧柔红霉素）联合治疗的情况。患者纳入标准为年龄18～75岁，并且考虑接受强化诱导化疗。除了R/R疾病之外，患者之前不能接受超过1次的干细胞移植或接受试验方案中用于诱导的化疗方案。 Uproleselan是一种在研的、第一类E-选择素拮抗剂，已获得FDA的突破性疗法和快速通道认定，可用于治疗R/R AML成人患者。E-选择素是一种白细胞粘附分子，在血管和骨髓的内皮细胞上连续表达。有证据表明，在AML中，骨髓微环境（BME）保护性龛中的内皮细胞与白血病干细胞和原始细胞之间的E-选择素-配体相互作用会促进白血病细胞的存活，并使其免受AML疗法的影响。Uproleselan旨在破坏E选择素的结合，防止白血病髓系细胞利用骨髓微环境的保护龛。 ALTO-100 2024年10月22日，Alto Neuroscience发布其在研疗法ALTO-100治疗重度抑郁症（Major depressive disorder）Ⅱb期研究未达到其主要终点。该临床试验结果的公布使得2月份刚刚登陆资本市场的Alto股价在周二晚间的盘后交易中下跌了76%，市值也仅剩1.2亿美金。 ALTO-100是由Alto Neuroscience利用其生物标志物平台所开发的一款口服药物，其靶标为脑源性神经营养因子（BDNF），可恢复患者的神经可塑性，使大脑能够灵活适应新信息。Alto Neuroscience的核心管线ALTO-100最初来自于Palisade Bio的管线NSI-189，2021年时转让给了Alto Neuroscience（交易总额490万美元，预付款50万美元）。Alto Neuroscience在2024年2月初以其独特的精准精神病学平台成功上市，筹集了1.286亿美元。然而，仅仅9个月后，其利用人工智能生物标志物平台所开发的ALTO-100的Ⅱb期试验中未能达到预期效果。 该Ⅱb期试验是一项双盲实验，在美国进行，共有301名成年人参与，在治疗期间，参与者基于生物标志物被分成治疗组和安慰剂组，将从第1天到第42天每天给药两次ALTO-100片剂，同时安慰剂组给予两次安慰剂。为了评估ALTO-100与安慰剂对中度至重度抑郁症的疗效，通过蒙哥马利-奥斯伯格抑郁量表（MADRS）总分衡量第1天到第42天的变化。主要终点是比较6周治疗期结束时ALTO-100组与安慰剂组的MADRS评分。Alto称ALTO-100的安全性和耐受性符合预期，但ALTO-100给药组的患者在抑郁症状方面没有表现出统计学上的显著改善，该治疗也没有达到其他预先指定的关键次要终点。 SPR720 2024年10月29日，Spero Therapeutics宣布，由于其候选抗生素SPR720（Fobrepodacin，一种正在研究的非结核分枝杆菌肺病小分子治疗药物，图1）的Ⅱa期研究的中期分析未达到主要终点。公司暂停该项目，内部重组裁员约39%。 图1：SPR720的化学结构式 Spero Therapeutics公司的SPR720在Ⅱa期试验中表现不佳。中期分析显示了这款口服抗生素候选药物的双重打击：既未能胜过安慰剂，又显示出肝脏毒性的迹象。中期分析显示与安慰剂的对比——对其疗效投下了重大怀疑——以及引起对SPR720安全性担忧的不良事件。在每天口服1000mg SPR720的人中，Spero看到了潜在的剂量限制性安全问题。安全问题包括三例可逆的3级肝毒性。由于疗效不佳和令人担忧的安全性，Spero决定暂停其当前的开发项目。 2016年Spero从Vertex公司以50万美元预付款获得了SPR720，认为它有潜力成为非结核性分枝杆菌肺病的口服治疗药物。 【参考资料】 1. Informa数据库, 检索日期: 2024年11月19日. 2. 药渡数据库, 检索日期: 2024年11月30日. 3. 药明康德、医药魔方、学术经纬、医药观澜、医麦客等网络公开资源. 本文其它内容请见《全球药物创新快讯》2024年第10期（总第146期）。

Phase 3 PIVOT-PO trial of tebipenem HBr remains on track to complete enrollment in 2H 2025 Reiterate cash runway into mid-2026; Q3 2024 ending cash balance of $76.3M CAMBRIDGE, Mass., Nov. 14, 2024 (GLOBE NEWSWIRE) -- Spero Therapeutics, Inc. (Nasdaq: SPRO), a multi-asset clinical-stage biopharmaceutical company, focused on identifying and developing novel treatments for rare diseases and multi-drug resistant (MDR) bacterial infections, today announced financial results for the third quarter ended September 30, 2024, and provided a business update. “Enrollment in the Phase 3 tebipenem HBr trial is progressing well, and we are on track to complete enrollment in the second half of 2025. Further, our work on the Phase 2 ready SPR206 program continues, contingent on availability of non-dilutive funding,” said Sath Shukla, President and Chief Executive Officer of Spero. “With SPR720 development plans now suspended while we complete a review of the full dataset from the Phase 2a trial, our extended cash runway into mid-2026 and streamlined operations position us well to achieve our ultimate goal of delivering new therapies to patients in need.” Pipeline Update Tebipenem HBr Tebipenem HBr is an investigational oral carbapenem antibiotic being developed for the treatment of complicated urinary tract infections (cUTI) including acute pyelonephritis (AP) to help patients potentially avoid hospitalizations or reduce duration of in-patient therapy. Spero granted GSK an exclusive license to commercialize tebipenem HBr in all territories, except certain Asian territories. Enrollment on track in PIVOT-PO, the global Phase 3 clinical trial of tebipenem HBr in patients with cUTI. This randomized, double-blinded trial compares oral tebipenem HBr with intravenous imipenem cilastatin, in hospitalized adult patients with cUTI/AP. The primary endpoint is overall response (a combination of clinical cure and favorable microbiological response) at the Test-of-Cure (TOC) visit. Target enrollment for the trial is approximately 2,648 patients, with enrollment completion expected in the second half of 2025. For more information on PIVOT-PO, refer to ClinicalTrials.gov ID NCT06059846. SPR206 SPR206 is an investigational, intravenously administered next-generation polymyxin that has shown antibiotic activity against MDR Gram-negative pathogens, including carbapenem-resistant Enterobacterales, Acinetobacter baumannii and Pseudomonas aeruginosa in preclinical studies. The U.S. Food and Drug Administration (FDA) has cleared the Company's IND for a Phase 2 trial in patients with hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP). The Company maintains its guidance to initiate the trial contingent on availability of non-dilutive funding. SPR720 SPR720 is an investigational oral, chemically stable phosphate ester prodrug that is converted rapidly in vivo to SPR719, the active moiety. SPR719 targets the ATPase site of DNA gyrase B in mycobacteria. In October 2024, a planned interim analysis of the Phase 2a proof-of-concept study of SPR720 for the treatment of nontuberculous mycobacterial pulmonary disease (NTM-PD) demonstrated that the study did not meet its primary endpoint. While the data showed antimicrobial activity associated with SPR720, the interim analysis did not show sufficient separation from placebo and highlighted potential dose limiting safety issues in patients dosed at 1,000 mg orally once daily, including three cases of reversible grade 3 hepatotoxicity. In evaluating the totality of both the efficacy and safety data, the Company suspended its development program for SPR720 and will evaluate other potential paths forward as the remaining data are collected and analyzed. Corporate Update In October 2024, following suspension of the current SPR720 development plans, Spero underwent a restructuring and reduction in force of approximately 39%, which extended the Company’s cash runway into mid-2026. Third quarter 2024 Financial Results Spero reported a net loss of $17.1 million, or ($0.32) per share of common stock, basic and diluted, for the third quarter ended September 30, 2024, compared with a net loss of $3.2 million, or ($0.06) per share of common stock, basic and diluted, for the third quarter ending September 30, 2023.Total revenue for the third quarter of 2024 was $13.5 million, compared with total revenue of $25.5 million for the third quarter of 2023. The revenue decrease for the third quarter of 2024 was primarily due to lower revenues related to ongoing collaborations.Research and development expenses for the third quarter of 2024 were $26.9 million, compared to $16.4 million of research and development expenses for the same period in 2023. The increase in research and development expenses year-over-year was primarily due to increased clinical trial expenses for PIVOT-PO.General and administrative expenses for the third quarter of 2024 were $5.2 million, compared to $5.7 million of general and administrative expenses for the same period in 2023. This year-over-year decrease was primarily due to decreased consulting and professional expenses.As of September 30, 2024, Spero had cash and cash equivalents of $76.3 million. Following the reduction in force and restructuring described above, Spero estimates that its existing cash and cash equivalents, together with earned and non-contingent development milestone payments from GSK, as well as other non-dilutive funding commitments, will be sufficient to fund its operating expenses and capital expenditures into mid-2026. For further details on Spero’s financials, refer to Spero’s Quarterly Report on Form 10-Q, filed with the U.S. Securities and Exchange Commission (SEC) today. About Spero Therapeutics Spero Therapeutics, headquartered in Cambridge, Massachusetts, is a multi-asset clinical-stage biopharmaceutical company focused on identifying and developing novel treatments for rare diseases and MDR bacterial infections with high unmet need. For more information, visit www.sperotherapeutics.com Government Agency Research Support The views expressed in this press release are those of the authors and may not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government. Tebipenem HBr Research Support Select tebipenem HBr studies have been funded in part with federal funds from the Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority, under contract number HHSO100201800015C. Department of Defense Select SPR206 studies are supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Joint Warfighter Medical Research Program under Award No. W81XWH 19 1 0295. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. National Institute of Allergy and Infectious Disease Select SPR206 studies have been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. 75N93021C00022. Forward Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding the timing, progress and results of Spero's preclinical studies, clinical trials and research and development programs; the potential benefits of any of Spero’s current or future product candidates in treating patients; and Spero’s strategy, goals and anticipated financial performance, milestones, business plans and focus. In some cases, forward-looking statements may be identified by terms such as "may," "will," "should," "expect," "plan," "aim," "anticipate," "could," "intent," "target," "project," "contemplate," "believe," "estimate," "predict," "potential" or "continue," the negative of these terms or other similar expressions. Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of important risks, uncertainties and other factors that may cause actual results to differ materially from those indicated by such forward looking statements, including whether tebipenem HBr, SPR720 and SPR206 will advance through the clinical trial process on a timely basis, or at all, taking into account the effects of possible regulatory delays, slower than anticipated patient enrollment, manufacturing challenges, clinical trial design and clinical outcomes; whether the results of such trials will warrant submission for approval from the FDA or equivalent foreign regulatory agencies; whether the FDA will ultimately approve tebipenem HBr and, if so, the timing of any such approval; whether the FDA will require any additional clinical data or place labeling restrictions on the use of tebipenem HBr that would delay approval and/or reduce the commercial prospects of tebipenem HBr; whether a successful commercial launch can be achieved and market acceptance of tebipenem HBr can be established; whether results obtained in preclinical studies and clinical trials will be indicative of results obtained in future clinical trials; Spero's reliance on third parties to manufacture, develop, and commercialize its product candidates, if approved; Spero's need for additional funding; the ability to commercialize Spero's product candidates, if approved; Spero's ability to retain key personnel; Spero's leadership transitions; whether Spero's cash resources will be sufficient to fund its continuing operations for the periods and/or trials anticipated; and other factors discussed in the "Risk Factors" set forth in filings that Spero periodically makes with the SEC. The forward-looking statements included in this press release represent Spero's views only as of the date hereof and should not be relied upon as representing its views as of any subsequent date. Except as required by law, Spero explicitly disclaims any obligation to update any forward-looking statements. Investor Relations Contact:Shai Biran, PhDSpero Therapeutics IR@Sperotherapeutics.com Media Inquiries: media@sperotherapeutics.com Spero Therapeutics, Inc.Condensed Consolidated Balance Sheet Data(in thousands)(Unaudited) September 30, December 31, 2024 2023Cash and cash equivalents$76,290 $76,333Other assets 58,871 106,057Total assets$ 135,161 $ 182,390 Total liabilities 69,654 75,496Total stockholder's equity 65,507 106,894Total liabilities and stockholders' equity$ 135,161 $ 182,390 Spero Therapeutics, Inc.Condensed Consolidated Statements of Operations(in thousands, except share and per share data) (unaudited) Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 Revenues: Grant revenue$5,650 $2,091 $14,893 $5,349 Collaboration revenue - related party 7,754 23,164 17,721 24,200 Collaboration revenue 65 218 319 710 Total revenues 13,469 25,473 32,933 30,259 Operating expenses: Research and development 26,864 16,393 67,921 34,883 General and administrative 5,198 5,708 16,648 19,121 Impairment of long-term asset — 5,306 — 5,306 Total operating expenses 32,062 27,407 84,569 59,310 Loss from operations (18,593) (1,934) (51,636) (29,051)Other income (expense) 1,156 940 3,668 2,877 Net loss (17,437) (994) (47,968) (26,174)Income tax expense 290 (2,211) 290 (2,211)Net loss$(17,147) $(3,205) $(47,678) $(28,385) Net loss per share attributable to common shareholders per share, basic and diluted$(0.32) $(0.06) $(0.89) $(0.54) Weighted average shares outstanding, basic and diluted: 54,124,862 52,710,280 53,869,824 52,603,709